Sweet Love …


Sweet love, renew thy force; be it not said

Thy edge should blunter be than appetite,

Which but to-day by feeding is allay’d,

To-morrow sharpen’d in his former might:

No prize for knowing I didn’t write those lines — or even that they’re down to The Bard of Avon. What he was on about here is the distinction between genuine (sweet) love and lust (appetite), the problem being that the latter may be assuaged today but will surely return tomorrow. Had we, by some Star Trek-like device, been able to secure his services for this piece, Shakespeare, master of the double-entendre, would quickly have spotted an opportunity in his new role as pop-sci scribe. For sweet read sugar: for appetite addiction.

Gary Taubes considers sugar to be the root of most western illnesses. Photograph: Alamy

The combination can be toxic, as the estimable US journalist Gary Taubes has argued over the last 15 years. His latest book The Case Against Sugar has just come out and I’m keen to give it a plug. In so doing I should point out that we’ve also done our best in these pages to make the same case — particularly in relation to cancer. However, it’s a little while since we wrote specifically on sugar, diet and cancer, mainly because nothing really new has caught my eye. Reading again the most relevant of our blog stories I thought they did a pretty good job (as Shakespeare might have said, being a chap not known for modesty). Three I thought worth looking at again are:

Biting the Bitter Bullet: how obesity and cancer quite often come hand-in-hand and how it is that we’re seduced into eating more and more of something that can help us get fat and ill.

A Small Helping For Australia: makes the point that this is a global problem (even though Australia’s wonderful).

The Best Laid Plans in Mice and Men..: artificial sweeteners aren’t the solution – just another problem.

Actually, there is one recent result we might mention — from Ken Peeters, Johan Thevelein & colleagues at the University of Leuven. Bearing in mind the long-established ‘Warburg effect’ by which cancer cells switch the energy supply system that breaks down glucose from respiration (using oxygen) to fermentation (making lactate), they looked at yeast cells that grow fastest when they ferment — much as cancer cells grow quicker than normal cells. Rather remarkably, they discovered a hitherto unknown way in which fermentation links to a key pathway controlling cell proliferation. That pathway centres around a protein called RAS that we met in Mission Impossible.

This finding does not show that eating lots of sugar gives you cancer but what it does show is a way by which, if yeast cells ‘eat’ more sugar, they grow faster. It seems quite possible that the underlying mechanism might work in human cells (the human version of the protein that links sugar metabolism to RAS, called SOS1, works in yeast) — giving an explanation for the well-known fact that the more sugar you eat the fatter you are likely to become. And what we do know is that obesity does raise cancer risk.

I dare say Gary might reckon this result worth a footnote in the second edition of: The Case Against Sugar by Gary Taubes is published by Portobello Books (£14.99).


Peeters, K. et al., (2017). Fructose-1,6-bisphosphate couples glycolytic flux to activation of Ras. Nature Communications 8, Article number: 922 doi:10.1038/s41467-017-01019-z.


Clocking In With Cancer Treatment

I always hesitate to say things like ‘you may recall’ as, from much undergraduate teaching, I’ve learned that blithe throwaways like ‘you’ll remember this from last Monday’s lecture’ tend to be met with blank stares and trying ‘you met this idea in the first year’ on second year classes will draw forth outright mirth blending with mutinous howls. So let’s just start by noting that three weeks ago in Our Inner Self we had a march-past of our intestinal army of bacteria and saw that it is in continuous flux, its make-up oscillating in time to our biological clock – the daily variation that governs most of our bodily functions including the sleep-wake cycle. That’s amazing stuff but a sharp bit of lateral thinking raises interesting questions. If most of the important things in our bodies tick to circadian rhythms, is cell proliferation one of them – after all, the process of cells making more of themselves is at the heart of life. Answer ‘yes.’ But, as abnormal cell proliferation – i.e. something going wrong – is a perfectly adequate three-word definition of cancer, a small step extends the question to ‘do tumours also have rhythm?’ Answer, again, ‘yes.’ A little background before we explain.

Turning back to the clock

In Twenty more winks we saw that there’s a connection between sleep (or rather lack of it) and cancer and showed how two pairs of genes (CRY/PER and CLOCK/BMAL1) lie at the core of circadian timekeeping. They control the sleep-wake cycle and much else. The proteins they make form an orchestrated feedback loop, synchronised by light-induced signalling. That is, the expression of each pair oscillates with a period of roughly 24 hours, but the pairs are out of step to the tune of about 12 hours. The proteins encoded by these genes regulate the expression of many other genes that ensure the cells and tissues of the body beat to an appropriate rhythm. Many messengers spread circadian oscillations around the body via the blood of which, in humans, cortisol (made by the adrenal glands) is perhaps the most familiar (it’s a steroid hormone: the medication dexamethasone is cortisol with two small, extra bits that make it 25 times more potent). You can fairly easily measure cortisol concentration in blood and you’d expect to find that at nine in the morning you’d have roughly double your midnight amount. In other words cortisol is part of your wake-up call. It turns on your appetite, gets you geared up for physical activity and it also activates anti-stress and anti-inflammatory signal pathways. EGFR & cortisol Cross-talk between EGFR and cortisol during the active phase (right: high cortisol) and the resting phase (left: low cortisol). (from Lauriola et al., 2014).

Getting the message across

Taking the memory-prodding risk yet again, in Mission Impossible? we described how biological signals from the outside world bind to receptors (proteins) to convey their message (I’m here, do something!) to the interior of cells. So the picture is: cells receive many signals from messengers that, one way or another, talk to the nucleus, switching on genes that drive proliferation. Most external messengers are proteins themselves – one example is a potent growth promoter called epidermal growth factor (EGF) that works by switching on the EGF receptor (EGFR). Cortisol isn’t a protein: as we’ve noted, it’s a steroid – which means it can diffuse across membranes – but, once inside a cell it works in essentially the same way, by binding to its specific receptor. The upshot of all this is that messengers transmit information from outside the cell to the nucleus – where DNA lives, the cells’ repository of genetic material – so that genes become activated to produce proteins.

Oscillating signals: cellular chattering

The picture of multiple, linear signalling pathways co-existing within cells invites the idea that their protein components might be unable to resist tapping in to their neighbours’ conversations – and so it has turned out. However, for pathways like the EGFR that signal cell growth, cross-talk with cortisol signalling is more than merely listening in. Proteins activated by the steroid hormone can actually interfere with the relays in the EGFR pathway so that EGF signals are suppressed during the active phase (day-time in us, night-time in rodents) but enhanced during the resting phase.

The meaning for life

So growth signaling is under circadian control – by and large our cells do their multiplying when we are at rest. Interesting although perhaps not unexpected. But, as The Bonzo Dog Doo-Dah Band warbled, ‘here comes the twist’ (Urban Spaceman, 1968 if you’re struggling). These pathways are the very ones that are hyper-activated (i.e. mutated) to drive cancer cells to make more of themselves and they are, accordingly, the targets for many anti-cancer drugs. However, chemotherapy is usually administered as single bursts, at daily or longer intervals, and drugs are progressively removed by metabolism thereafter. This means that much of the impact may be lost if, when the drug concentration is at its highest, the target pathway is already suppressed by high glucocorticoids . There’s evidence consistent with this idea from animals bearing EGFR-driven tumours treated with specific inhibitors that are more effective if administered in the resting phase rather than in the active phase.

It’s all in the timing

So two new messages are now making themselves heard in the world of cancer biology. The first is beginning to tell the full story of clock complexity. The second takes up this theme by pointing out that a circadian clock-based model in cancer therapy may offer improved methods for prevention and treatment.


Lauriola, M. et al. Diurnal suppression of EGFR signalling by glucocorticoids and implications for tumour progression and treatment. Nat. Commun. 5:5073 doi: 10.1038/ncomms6073 (2014).

Taking the MYC out of cancer

It has been famously said, though no one quite knows who gave first utterance, that England and America are two nations divided by a common language. In deference to readers from the US of A, therefore, we need a word about English before we embark on the current topic. You can get quite a long way in the States on an English accent, partly because the inhabitants are, by and large, very tolerant and cosmopolitan souls and also because they perceive Brits as being rather weird but harmlessly entertaining – at least since they gave up the idea of owning America, signed the Treaty of Paris and slung their hook. But that last phrase is an example of how things can get sticky when you talk to an American audience and it slips your mind that 1783 was quite a long time ago – long enough in fact for a good deal of divergent language evolution. Put another way, use idioms unthinkingly and you can die the death – leaving your listeners wishing that you would indeed sling your hook (American translation: beat it). One of the odder things about this linguistic separation is that American doesn’t have a good phrase that means gently making fun of someone. You can pull a Yankee leg it is true and you may mess them about – but that one’s really fraught as it carries a different innuendo in English. So it’s a pity that over there you can’t extract the Mick, take the Mickey or remove the Michael. It’s deeply regrettable that this phrase probably owes its origins to Cockney rhyming slang referring to the act of urination but strawberries grow in manure and all that. Similar pratfalls work in the other direction, of course, and British audiences are likely to look blank if you mention your keister: start talking about booty and mussing with someone and they’ll really be baffled.

To the current topic. We saw in Mission Impossible that many different pathways pass signals saying ‘grow’ from the outside world to the nucleus at the centre of a cell. Many of these relays use RAS proteins – they’re a major junction in the cellular network so they’re a very tempting target for disruption of signaling. But if all roads lead to Rome, so to speak, is there not an even better target – a main gate, the critical portal through which everything that drives cell proliferation must pass? There is and it’s called MYC (pronounced ‘mick’ – Ah! Now all is clear!!), the gene encoding a protein of the same sound that is a unique master regulator. MYC coordinates the expression of a large panel of genes involved in cell growth and division – it’s essential for cell proliferation.

 MYC pic

Cell signaling. Many messengers turn on lots of relays that focus on the nucleus telling cells to grow and divide. The MYC protein is a master coordinator.

But there’s an obvious problem: to survive we need to make new cells all the time – about one million every second, just to maintain the status quo. It seems hardly worth pointing out that if you gave someone a drug that blocked MYC it would be fatal: the body simply couldn’t survive for very long with a blocked cell production line. Indeed it’s been known for some time that knocking out the MYC gene in mice is fatal: they fail to develop beyond an early embryonic stage. And yet there’s a huge temptation to ask ‘What would inhibiting MYC do to tumors: might it actually kill them?’ – a curiosity fuelled by the knowledge that MYC is deregulated in most – perhaps all – cancers. That is, an almost invariable upshot of the mutation patterns found in tumors is that excessive amounts of MYC protein are made – and, as it drives cells round the cell cycle and into division, more MYC equals abnormal cell growth, aka cancer.

So, in an experiment that all logic said would not work, Gerard Evan and his colleagues in San Francisco and Cambridge devised a way to switch on an inhibitor of MYC in transgenic mice to ask the unaskable: ‘Is blocking MYC fatal and, if is isn’t, what does it do to tumors?’ The method is to use a trick of genetic engineering to give mice a novel gene that is switched on by dosing them with a drug added to their drinking water. Omitting the drug switches it off. The gene encodes a protein that sticks to the MYC protein and prevents it from interacting with its normal partner so that the dynamic duo that drives cell growth can’t be formed.

The results were startlingly dramatic. First of all, MYC blockade didn’t kill the mice although it certainly had some effects. A shaved patch of fur doesn’t re-grow quickly as it normally would and males become infertile because they can’t make new sperm. But the mice aren’t aware of these little problems and in general are as full of beans as their chums with normal levels of MYC activity – and in any case these mild effects are reversible. Switch off the MYC block and they return rapidly to normal.

That was surprising enough but the really staggering result came from introducing the MYC blockade into mice that develop lung tumors (driven by the expression of a mutant RAS gene). Inhibition of MYC has an almost immediate effect on tumor size: tumors regress and the side effects remain mild and reversible. A single burst of MYC blockade results in a significant extension of life span for tumor-bearing mice. Even more remarkable, successive episodes of MYC inhibition (a ‘metronomic’ regime) leads to the gradual eradication of the tumors – and the elimination of lung cancer means that the mice now have a normal life span.

It should be emphasized that so far this has only happened in mice and the Appian Way of cancer therapy is littered with the corpses of brilliant ideas that worked a treat in those wonderful little models but were utterly useless when it came to humans. However, science is the practice of eternal optimism and there are sound grounds for hope here. Switching a gene on and off by genetic engineering is fine in mice. It won’t do for us but already some small molecule inhibitors have been made that appear to work in mice. The hope is that both the anti-cancer effect and the mild side-effects will be recapitulated in humans – and that, because all pathways do indeed lead to it, taking the MYC out of cancer will kill tumours. Then the really optimistic bit – that even crafty cancer cells will be unable to find a way round such a block. Because all proliferation signals lead to MYC there will be no adaptive mechanism to which cells can turn to ensure their survival.

In short, the tumour will be stuffed – which rather brings us back to where we started except that, having taken the MYC, this needs no translation.


Soucek, L., Whitfield, J.R., Sodir, N.M., Massó-Vallés, D., Serrano, E., Karnezis, A.N., Swigart, L.B. and Evan, G.I. (2013). Inhibition of Myc family proteins eradicates KRas-driven lung cancer in mice. Genes Dev., 27, 504-513.